The longterm goal of this project is to utilize cytomegalovirus (CMV) vectors carrying oncogenes of high risk human papillomaviruses (HPV) as novel therapeutic vaccines against cervical cancer. Although recently launched prophylactic vaccines protect against HPV infection, these VLP-based vaccines have not demonstrated significant benefit for individuals who are already infected with HPV. Thus, there is an urgent need, and a sizable market, for a therapeutic HPV vaccine capable of controlling or eliminating ongoing infections with HPV. However, the development of therapeutic HPV vaccines has been challenging since such a vaccine must generate sustained high level effector T cell responses in the cervical epithelium that specifically recognize the E6 and E7 non-structural proteins of high risk HPV. TomegaVax believes that CMV vectors are uniquely qualified for this task because CMV is the only known vector capable of inducing lifelong, high frequencies of effector memory T cell (TEM) responses to heterologous antigens. In contrast to central memory T cells induced by conventional vaccines, TEM maintained by persistent, low level antigen presentation by CMV, generates a continuous immune shield in peripheral sites of pathogen entry, including the cervix. In non-human primate models, TEM induced by CMV-vectored vaccines have shown unprecedented protection against simian immunodeficiency viruses, including when challenged intra-vaginally. In fact, protected animals are functionally cured, suggesting a longterm therapeutic effect of CMV-based vaccines. In the human population, CMV is highly prevalent establishing lifelong persistent infection that is asymptomatic. However, unlike traditional viral vectors, CMV vectors can be used repeatedly even in individuals that have already mounted an immune response against CMV. Moreover, CMV vectors engineered to be spread-deficient maintain TEM stimulation so that potential CMV pathogenesis upon immunosuppression can be completely avoided. In this feasibility study, we will therefore determine whether CMV-vectored HPV vaccines are protective employing murine models to test immunotherapies against HPV tumor antigens. Mice will be vaccinated with wild-type or spread-deficient murine CMV carrying constructs expressing epitopes of the oncogenes E6 and E7 of HPV and challenged with E6/E7 expressing transformed epithelial cells. We expect that CMV/HPV vaccines will prevent tumor formation or potentially even reverse tumor growth.